Differentiation, growth, and function of eukaryotic cells are coordinated with various mechanisms which regulate DNA replication and prevent excessive proliferation. While uncoordinated cell proliferation can cause cancer, autoimmune diseases, and inflammatory diseases, programmed cell death or apoptosis removes excessive or damaged cells without causing tissue destruction and inflammatory response. A plethora of genes, named oncogenes, have been identified with cancer. Several highly conserved processes have been shown to regulate apoptosis.
bcl-2 proto-oncogene is a repressor of apoptosis and functions downstream in the regulation of cell-death processes. The C. elegans homolog of Bcl-2, CED-9, represses the apoptosis of 131 cells during the nematode development (Hengartner, M. O. and Horvitz, H. R. (1994) Cell 76: 665-676). Several Bcl-2-related proteins, such as Bax, Bcl-X.sub.L, and Bad, share homology with Bcl-2 mostly within two conserved regions, named BH1 and BH2. Bcl-X.sub.L and Bcl-2 are shown to repress apoptosis, while Bax and Bad promote apoptosis. Specifically, Bax is capable of dimerizing with Bcl-2 and Bcl-X.sub.L, whereas Bad is able to dimerize with Bcl-X.sub.L but not with Bcl-2. When Bax dimerizes with Bcl-2, the apoptosis-inhibiting function of Bcl-2 is suppressed (Oltvai, Z. N. et al. (1993) Cell 74: 609-619; Yin, X.-M. et al. (1994) Nature 369: 321-323). Similarly, when Bad displaces Bax and dimerizes with BCl-X.sub.L, the apoptosis-repressive activity of Bcl-X.sub.L is inhibited (Yang, E. et al. (1995) Cell 80: 285-291).
Leucine-rich repeat (LRR) is a structural motif of about 20 to 29 amino acid residues in length associated with protein-protein interactions. The motif contains leucine or other aliphatic residues at positions 2, 5, 7, 12, 16, 21, and 24 and asparagine, cysteine or threonine at position 10. X-ray structure determination of LRR motifs suggests that each LRR is composed of a .beta.-sheet and an .alpha.-helix.
p37NB is a 37 kDa LRR protein identified in human neuroblastoma cells (Kim, D. et al. (1996) Biochim. Biophys. Acta 1309: 183-188). Northern blot hybridization and RT-PCR studies show that p37NB is differentially expressed in several neuroblastoma cell lines. A related LRR protein, PRELP, is characterized as a 42 kDa secreted protein (Bengtsson, E. et al. (1995) J. Biol. Chem. 270: 25639-25644). PRELP consists of 10 LRR motifs ranging in length from 20 to 26 residues with asparagine at position 10. Northern analysis shows differential expression of PRELP in various tissues.
MA-3 or TIS is a mouse protein associated with apoptosis (Shibahara, K. et al. (1995) Gene 166: 297-301; Onishi, Y. and Kizaki, H. (1996) Biochim. Biophys. Res. Commun. 228: 7-13). The nucleotide sequence of the mouse proteins predicts an amino acid sequence of 469 residues. MA-3 is highly expressed in thymus and is present in all apoptosis-inducible cell lines including thymocytes, T cells, B cells, and pheochromocytoma (Shibahara et al, supra). TIS expression is down-regulated in the RVC lymphoma cells incubated with an topoisomerase I inhibitor, an antitumor drug, and the low expression level of TIS may be a contributing factor to the cytotoxicity of the topoisomerase inhibitors (Onishi and Kizaki, supra).
The discovery of three new human proteins associated with cell proliferation and the polynucleotides encoding them satisfies a need in the art by providing new compositions which are useful in the diagnosis, prevention, and treatment of disorders associated with abnormal cell proliferation and apoptosis.